The accumulating evidence strongly indicates that the descending pain control systems activated by various opioids for antinociception involve multiple descending pathways and different neurotransmitter systems. It is hypothesized that the descending pain control systems can be classified at least into three descending systems: 1) epsilon receptor mediated, 2) mu receptor mediated, and 3) kappa receptor mediated descending systems. The epsilon system is activated by beta-endorphin and the antinociception is mediated by the release of Met-enkephalin and the subsequent stimulation of opioid delta receptors in the spinal cord. The mu system is stimulated by morphine or DAMGO and the antinociception is mediated by the activation of spinopetal serotonergic and noradrenergic systems and stimulation of 5-HT receptors and alpha2- adrenoceptors in the spinal cord. The kappa system is activated by U50,488H or other kappa receptor agonists and the antinociception is mediated by the releases of 5-HT and dynorphin A (1-17) and stimulation of 5-HT receptors and kappa receptors in the spinal cord. The aims of the present proposal are a) to further characterize these three descending pain control systems, b) to study the interactions of these three descending systems with other neurotransmitter systems such as CCK, excitatory amino acids and GABA and c) to study the involvements of NO-cGMP and G-proteins on epsilon, mu and kappa system mediated antinociception. The specific aims are described below: 1) Studies of antinociceptive effects induced by epsilon, mu and kappa receptor agonists given i.c.v.; 2) Search for nonpeptide opioids which produce antinociception by selectively activating the epsilon system; 3) Mapping of the brain sites sensitive to beta-endorphin, morphine, DAMGO and bremazocine for the production of antinociception and identification of receptor types in the spinal cord involved in antinociception induced by each selective opioid receptor agonists injected intracerebrally at appropriate brain sites; 4) Delineation of the neural pathways for descending epsilon, mu and kappa systems activated by beta-endorphin, morphine and U50,488H, respectively; 5) Characterization of the released Met-enkephalin, dynorphin A and other neuropeptides from the spinal cord induced by beta-endorphin, U50,488H and other opioids with different opioid receptor activities; 6) Studies of the neural mechanisms of the antagonistic interaction of CCK in the spinal cord with the epsilon system; 7) Studies of the neural mechanisms of NO-cGMP system by L- arginine or other NO donors in potentiating epsilon receptor mediated antinociception; 8) Studies of the involvement of NMDA and non-NMDA receptors on the antinociception induced by beta-endorphin, morphine and other opioid receptor agonists; 9) Studies of the activation of GABA receptors in the brain on the antinociception induced by beta-endorphin, morphine and other opioids; and 10) Blockade of alphai/alphao and alphas of G-protein by pertussis toxin and cholera toxin, respectively, on epsilon, mu and kappa system mediated antinociception. The antinociception will be assessed mainly by the tail-flick and hot-plate tests. Met-enkephalin and other neuropeptides will be measured by radioimmunoassay. Mice and rats will be used for the studies.